Hookworm Disease

Human hookworm disease is a common helminth infection worldwide that is predominantly caused by the nematode parasites Necator americanus and Ancylostoma duodenale; organisms that play a lesser role include Ancylostoma ceylanicum, Ancylostoma braziliense, and Ancylostoma caninum. Hookworm infection is acquired through skin exposure to larvae in soil contaminated by human feces. Soil becomes infectious around 5-10 days after contamination and remains so for 3-4 weeks, depending on conditions.[1]

Worldwide, hookworms infect an estimated 576-740 million people.[2]  Although most of those affected are asymptomatic,[3]  some may experience anemia and other complications.[4]  Hookworms may persist for many years in the host and impair the physical and intellectual development of children and the economic development of communities.

Historically, hookworm infection has disproportionately affected the poorest among the least-developed nations, largely as a consequence of inadequate access to clean water, sanitation, and health education. The frequent absence of symptoms notwithstanding, hookworm disease substantially contributes to the incidence of anemia and malnutrition in developing nations.[5]  It occurs most commonly in the rural tropical and subtropical areas of Asia, sub-Saharan Africa, and Latin America.[6]

Individual hookworm treatment consists of iron replacement and anthelmintic therapy. Community eradication has proven difficult, even with intensive, yearly, school-based programs. Part of the difficulty may be failure to clear infection from adults with high worm burden. Despite this, successful control and eradication of hookworms is a worthy goal for new methods that could offer huge economic and social benefits to much of Africa and Asia.

See Common Intestinal Parasites, a Critical Images slideshow, to help make an accurate diagnosis.

Hookworm life cycle

The life cycle of hookworms begins with the passing of hookworm eggs in human feces and their deposition into the soil.

Each day in the intestine, a mature female A duodenale worm produces about 10,000-30,000 eggs, and a mature female N americanus worm produces 5000-10,000 eggs. After deposition onto soil and under appropriate conditions, each egg develops into an infective larva. These larvae are developmentally arrested and nonfeeding. If they are unable to infect a new host, they die when their metabolic reserves are exhausted, usually in about 3-4 weeks.[2]

Larval growth is most proliferative in favorable soil that is sandy, moist, and covered from direct sunlight with an optimal temperature of 20-30°C.[7]  Under these conditions, the larvae hatch in 1 or 2 days to become rhabditiform larvae, also known as L1.

The rhabditiform larvae feed on the feces and undergo 2 successive molts; after 5-10 days, they become infective filariform larvae, or L3. These L3 go through developmental arrest and can survive in damp soil for several weeks.[8]  However, they quickly become desiccated if exposed to direct sunlight, drying, or salt water. L3 larvae live in the top 2.5 cm of soil and move vertically toward moisture and oxygen.

The L3 larvae are 500-700 µm long (barely visible to the naked eye) and are capable of rapid penetration into normal skin, most commonly through the hair follicles of the hands or feet.[5]  Transmission occurs after 5 or more minutes of skin contact with soil that contains viable larvae. The skin penetration may cause a local pruritic dermatitis, also known as ground itch. Ground itch at the site of penetration is more common with Ancylostoma than with Necator.

The larvae migrate through the dermis, entering the bloodstream and moving to the lungs within 10 days. Once in the lungs, they break into alveoli, causing a mild and usually asymptomatic alveolitis with eosinophilia. (Hookworms are among the causes of the pulmonary infiltrates and eosinophilia [PIE] syndrome, along with Ascaris and Strongyloides species.)

Having penetrated the alveoli, the larvae are carried to the glottis by means of the ciliary action of the respiratory tract. During pulmonary migration, the host may develop a mild reactive cough, sore throat, and fever that resolve after the worm migrates into the intestines. At the glottis, the larvae are swallowed and carried to their final destination, the small intestine.

During this part of the migration, the larvae undergo 2 further molts, developing a buccal capsule and attaining their adult form. The buccal capsule of an adult A duodenale has teeth to facilitate attachment to mucosa, whereas an adult N americanus has cutting plates instead. A muscular esophagus creates suction in the buccal capsule.

Using their buccal capsule, the adult worms attach themselves to the mucosal layer of the proximal small intestine, including the lower part of the duodenum, jejunum, and proximal ileum, but especially the distal jejunum. In so doing, they rupture the arterioles and venules along the luminal surface of the intestine.

The adult worms release hyaluronidase and other hydrolytic enzymes, which degrade intestinal mucosa and erode blood vessels, resulting in blood extravasation.[5]  They also ingest some blood. An anticoagulant facilitates blood flow by blocking the activity of factors Xa and VIIa. Adult worms also elaborate factors (eg, neutrophil inhibitory factor) that protect them from host defenses.

In 3-5 weeks, the adults become sexually mature, and the female worms begin to produce eggs that appear in the feces of the host.

Although N americanus infects only percutaneously, A duodenale can also infect by means of ingestion, including transmission through breast milk; however, in situ Ancylostoma may also lie dormant in tissues and later be reactivated and establish intestinal infections.[1]  This ability to enter dormancy in the human host may be an adaptive response evolved to increase the chances of propagation. If all larvae were to mature promptly during dry seasons of the year, females would release eggs onto inhospitable soil. Eggs produced and released during the wet season have a much greater chance of encountering optimal soil conditions for further development.

Neither Necator nor Ancylostoma multiplies within the host. If the host is not reexposed, the infection disappears after the worm dies. The natural lifespan for an adult A duodenale is about 1 year, and that for an adult N americanus is 3-5 years.

Types of hookworm disease

Hookworm infection gives rise to the following 3 clinical entities in humans:

• Classic hookworm disease - This is a gastrointestinal (GI) infection characterized by chronic blood loss that leads to iron-deficiency anemia and protein malnutrition; it is caused primarily by N americanus and A duodenale and less commonly by the zoonotic species A ceylanicum.

• Cutaneous larva migrans - This is an infection whose manifestations are limited to the skin; it is most commonly caused by A braziliense, whose definitive hosts include dogs and cats.

• Eosinophilic enteritis - This is a GI infection characterized by abdominal pain but no blood loss; it is caused by the dog hookworm A caninum

In cutaneous larva migrans, the infective larvae of zoonotic species such as A braziliense do not elaborate sufficient concentrations of hydrolytic enzymes to penetrate the junction of the dermis and epidermis. The larvae thus remain trapped superficial to this layer, where they migrate laterally at a rate of 1-2 cm/day and create the pathognomonic serpiginous tunnels associated with this condition. Larvae can survive in the skin for about 10 days before dying.[5]

In eosinophilic enteritis, A caninum larvae typically enter a human host by penetrating the skin, though infection by oral ingestion is also possible. Most of the time, these larvae remain dormant in skeletal muscles and create no symptoms. In some individuals, larvae may reach the gut and mature into adult worms.

Why some individuals sustain A caninum development and then respond with a severe localized allergic reaction is unknown. Adult worms secrete various potential allergens into the intestinal mucosa. Some patients have been reported to experience increasingly severe recurrent abdominal pain, which may be analogous to a response to repeated insect stings.

Clinical manifestations

Intestinal blood loss is the major clinical manifestation of hookworm infection.[9]  In fact, hookworm disease historically refers to the childhood syndrome of iron deficiency anemia, protein malnutrition, and growth and mental retardation with lethargy resulting from chronic intestinal blood loss secondary to hookworm infection in the face of an iron deficient diet.

Hookworms ingest and digest some of the blood from the injured mucosa by means of a multienzyme cascade of metallohemoglobinases. Each Necator worm ingests 0.03 mL of blood daily, whereas each Ancylostoma worm ingests 0.15-0.2 mL of blood daily. Inhibited host coagulation due to a series of anticoagulants directed against factor Xa and the factor VIIa–tissue factor (TF) complex, as well as against platelet aggregation, further exacerbates blood loss. Ancylostoma in particular is a wasteful feeder, with much more blood being lost than is actually ingested by the worm. In fact, most blood loss is a result of leakage around the hookworm attachment site rather than direct ingestion by the worm – moderate to heavy Necator infections can produce blood loss of over 1 mL per worm a day.[5]

The amount of blood loss and the degree of anemia are positively correlated with the worm burden, whereas hemoglobin, serum ferritin, protoporphyrin levels are significantly and negatively correlated with the number of worms.[10]  Threshold worm loads for anemia differ nationally, with as few as 40 worms producing anemia in countries with low iron consumption.

Generally, the extent of hookworm infection may be categorized as follows, according to the WHO:

• Light (< 1,999 eggs per gram of feces)

• Moderate (2,000-3,999 EPG)

• Heavy (>4,000 EPG)[5]

People who develop an initial heavy infection seem to reacquire heavy infection, and individuals who are lightly infected reacquire light infections. Since each adult worm is the molt of a single infective larva, this suggests continuing exposure to highly contaminated environments with little amnestic immunity in the host. Individuals with light infection have minimal blood loss and may have infection but not disease, especially if iron intake or reserves are adequate to compensate for the blood loss. Moderate-to-heavy infections cause iron-deficiency anemia.

In addition, because A duodenale both consumes more blood per worm and causes more leakage than N americanus does, the severity of anemia may differ as a factor of the hookworm species that is causing the infection. Blood loss as a result of A duodenale infection may be 10 times heavier than that from N americanus infection.[5]  Severe anemia affects intellectual and physical development in children and cardiovascular performance in adults.

Because of the clinically significant blood loss and the worms’ ingestion of serum proteins, hypoproteinemia may also develop, which is clinically manifested as weight-loss, anasarca, and edema.

This is the result of a protein-losing enteropathy, with immunoglobulins among the proteins lost as a result of worm digestion. This results in stunted growth, as well as an increased susceptibility to infections such as malaria and gastrointestinal infections with enteric bacteria, viruses, and protozoa. This protein-losing enteropathy can also contribute to a more rapid progression of an HIV infection. In patients with high enough iron intake, enteropathy may occur independent of anemia.

Hookworms appear to evade or inhibit effective human immune responses, including by secreting deoxyribonucleases to degrade neutrophil extracellular traps during penetration of the skin.[11]  The persistence of hookworm infection supports the theory that the worms have evolved adaptive molecular mechanisms to achieve a homeostatic balance with the host immune response.[12]

Little is known about the innate immune response to metazoan in general and hookworms in particular.[13]  Hookworm-derived pathogen-associated molecular patterns (PAMPS) of molecules are thought to react with receptors on dendritic cells or basophils to stimulate interleukin (IL)–4 and initiate an immunological cascade resulting in a type 2 regulatory response from Th2 helper cells. This may be augmented by “alarmins” such as thymic stromal lymphopoietin (TSLP), IL-33, and IL-25 released from epithelial cells damaged by worms. These activate newly described innate lymphoid type-2 cells (ILC2) that provide early rise in protective TH2 cytokines IL-5 and IL-13.

Meanwhile, worm products inhibit IL-12, and TSLP induces basophil production of IL-4, both promoting differentiation of Th2 cells. The antiparasite Th2 cells produce more IL-4, IL-5, and IL-13, which cause B cell immunoglobulin G type 1 (IgG1) and immunoglobulin E (IgE) class switching. Antiworm IgE binds the parasite and activates mast cells, which release inflammatory molecules, while IL-5 promotes eosinophil expansion and activation and M2 macrophage differentiation, which damage and produce granulomas, respectively. Other effector molecules include transforming growth factor-beta (TGF-b), resistinlike molecule (RELM)–alpha, chitinases, and matrix metalloproteases, all of which damage or limit the parasite.

At the same time, this intense Th2 immune response must be regulated by the host to avoid immunopathology, and by the parasite to allow survival. Helminths enhance expression of T cell co-inhibitory molecules that include PD-1 and CTLA-4, and promote differentiation of tolerogenic dendritic cells and T regulatory cells. T regulatory cells produce anti-inflammatory cytokines IL-10 and TGF-b. Hookworms also appear to secrete an inhibitor of natural killer cells, thereby suppressing production of interferon gamma and the Th2 response that would be expected to clear the parasite.

Since 1989 with David Strachan’s observation of a correlation between incidence of hay fever in children and low family size, the hygiene hypothesis has excited investigators as to a possible inverse relationship between helminth infections and allergic and autoimmune disease.

The increased prevalence of atopy, asthma, and food allergy in areas free of worm infestation has been cited as supportive of the hygiene hypothesis and has even prompted investigation of worms or worm products as therapy for such diseases. Similarly, areas of high hookworm endemicity have low rates of reaction to dust mite antigens. It is thought that worm-activated regulatory and counter-regulatory processes involving Th2 and T regulatory cells and cell products may paradoxically inhibit Th2 responses that in the absence of worms cause reactions to potential allergens.

In the search for possible vaccine targets, investigators have focused on hookworm molecular inhibitors of coagulation factors Xa and VIIa-TF and metalloproteases that degrade hemoglobin and intestinal mucosal cells. The Sabin Vaccine Institute has developed a 2 antigen human hookworm vaccine comprising recombinant Necator antigens Na- GST-1 and Na- APR-1, each of which is required for hookworm use of host blood.[14]  Phase I clinical trials conducted in Gabon for this vaccine showed no difference in adverse effects between the vaccine and placebo groups as well as production of IgG antibodies, indicating a safe and potentially effective vaccine, as of September 2020.[15]  Another antigen, Ancylostoma -secreted protein 2 (ASP-2), appears necessary for chemokine receptor binding and invasion and has shown some promise in animal vaccine trials. The 3-dimensional structure of Na-ASP-2 has recently been reported and identified as a conserved tandem histidine motif necessary for catalytic or proteolytic activity.[3]  Unfortunately, this vaccine produced urticarial reactions among previously infected recipients, and its development was halted.[16]

Causative organisms

Organisms that have been shown to cause hookworm disease include the following:

• Necator americanus

• Ancylostoma duodenale

• Ancylostoma ceylanicum

• Ancylostoma caninum

• Ancylostoma braziliense

N americanus is the globally predominant human hookworm and is the only member of its genus known to infect humans. It is a small, cylindrical, off-white worm; adult males measure 7-9 mm, and adult females measure 9-11 mm.[10]

A duodenale is more geographically restricted than N americanus and is one of several anthropophilic members of the genus Ancylostoma. Though it can live in the small intestines of cats and dogs, it primarily infects humans and is responsible for classic hookworm disease. A duodenale resembles N americanus in appearance but is somewhat larger, with adult males measuring 8-11 mm and adult females measuring 10-13 mm.

On microscopy, N americanus can be differentiated from A duodenale on the basis of the cutting plates that it possesses in place of teeth.

A ceylanicum primarily infects canines and felines but can cause milder classic hookworm disease in humans. A braziliense is a canine and feline hookworm that, in humans, causes cutaneous larva migrans, or creeping eruption, a self-limiting condition characterized by serpiginous burrows formed as the larvae migrate through the epidermis. A. caninum is a canine hookworm that mainly causes eosinophilic enteritis in humans (though it also causes cutaneous larva migrans in a minority of cases).

Risk factors

Poor sanitation, limited access to clean water, and low income and educational attainment are well-documented risk factors for hookworm infection. High-risk populations include international travelers, refugees, international adoptees, recent immigrants, and young children who have contact with soil or sand.[17]

Favorable environmental conditions are conducive to the development of hookworm disease. Optimal conditions for eggs include ambient temperatures of 20-30°C, although A duodenale is better adjusted to lower temperatures than N americanus, and warm, moist, well-aerated soil that is shielded from sunlight.[18]  These conditions occur during cultivation of numerous agricultural products; hence, hookworm infections occur primarily in rural areas. Larvae fail to develop in temperatures below 13°C and fully hatched eggs and new larvae are destroyed by temperatures below 6-8°C and above 45°C. They are also killed by drying and direct sunlight.

United States statistics

Although hookworm infection is now relatively rare in the United States, hookworm played an important role in the impoverishment of the southeastern region of the country until the 1930s and there are still endemic pockets of local hookworm transmission in some southeastern states.[19]  Studies performed in the early 1970s indicated prevalences as high as 14.8% among schoolchildren from rural Kentucky and as high as 12% among schoolchildren from rural coastal Georgia. A low prevalence of classic hookworm infection, mainly due to N americanus, is still found in pockets of the southeastern United States. A 2017 report demonstrated 35% prevalence of N americanus among 55 rural households in Lowndes County, Alabama, who depended on poorly functioning septic tank systems, suggesting continued vulnerability of rural poor populations, even today.[20]

Hookworm infection and disease are now most likely to be found in immigrants, refugees, and adoptees from tropical countries. Occasionally, people returning from travel abroad present with acute watery diarrhea with eosinophilia upon their return to the United States.

Cutaneous larva migrans is endemic in the southeastern states and Puerto Rico. The canine hookworm A caninum has reportedly caused eosinophilic enteritis in Australia and the United States.

International statistics

Human infection with A duodenale or N americanus is estimated to affect approximately 576-740 million people worldwide.[2]

Infection is most prevalent in tropical and subtropical zones, roughly between the latitudes of 45°N and 30°S; in some communities, prevalence may be as high as 90%. The disease flourishes in rural communities with moist shaded soil and inadequate latrines. Agricultural laborers have traditionally been at high risk. Improper disposal of human feces and the common habit of walking barefoot are key epidemiologic features. However, the use of footwear has not been shown to affect hookworm prevalence since the larvae can invade through any skin surface.

In 2010, it was estimated that approximately 117 million individuals in sub-Saharan Africa were infected with hookworms, as well as 64 million in East Asia, 140 million in South Asia, 77 million in Southeast Asia, 30 million in Latin America and the Caribbean, 10 million in Oceania, and 4.6 million in the Middle East and North Africa. Oceania has the highest prevalence (49%), followed by sub-Saharan Africa (13%), Southeast Asia (12.6%), South Asia (8.6%), East Asia (5%), and Latin America/Caribbean (5%).[21]  These represent approximately 20% decreases in prevalence from 2005 WHO estimates.

Infection is closely associated with poverty; inadequate sanitation, poor housing construction, and lack of access to essential medications are major factors in this relationship. Studies performed in Brazil indicate that the prevalence and intensity of infection is higher among poorer households. Furthermore, a recent study in the U.S. has found an infection prevalence in a poor, rural county in Alabama to be up to 34%.[22]  Similar studies in Uganda indicate that in comparison with the spotty geographic prevalence of ascariasis and trichuriasis, hookworm disease is more homogeneously distributed.[23]  Recycling human sewage for fertilizer is now being practiced on a large scale and could pose a risk for epidemic infection.[24]

As countries develop, the factors conducive to hookworm disease are mitigated, and hookworm infestation decreases. In developed countries, infection is most commonly encountered in travelers, immigrants, and adoptees from developing countries.

Hookworm has a global distribution, with both Necator and Ancylostoma found in Africa, Asia, Australia, and the Americas. However, only Necator is found in south India while only Ancylostoma is found in northern India, North Africa, and the Middle East. A ceylanicum is found in focally endemic areas in southern Asia and the Pacific Islands. N americanus predominates in southern China, Southeast Asia, the Americas, most of Africa, and parts of Australia. This differential distribution is not absolute, and mixed infections may occur in individual patients. Coinfection with Ascaris or Trichuris is common in many parts of the world.[4]

Age- and sex-related demographics

In endemic areas, the highest prevalences are reported among preschool and school-aged children and adolescents, possibly because of age-related changes in exposure and the acquisition of immunity.[6]  Once infected, children are more vulnerable to developing morbidity because dietary intake often fails to compensate for intestinal losses of iron and protein, especially in developing countries. A fulminant form of acute GI hemorrhage associated with acute Ancylostoma infection has been described in newborns.[25]

Although children bear a large disease burden, hookworm infection appears to have an atypical age distribution. Unlike other soil-transmitted helminth infections, such as ascariasis and trichuriasis (for which the incidence peaks in childhood), hookworm infection appears to increase throughout childhood until it reaches a plateau in adulthood.[26]  Egg counts in stool also increase in a similar pattern, though are typically higher in women than in men.[27]

Although adults carry larger worm burdens than children do and are generally more subject to disease, the relationship is nonlinear and depends on diet and activity thresholds. The increasing prevalence of hookworm disease and higher worm burden among adults in many infected communities, especially in China, suggests that hookworm is immunosuppressive, likely due to their excretory and secretory products.[28]

Males and females are equally susceptible to hookworm infection, though infected females tend to have higher egg counts in stool than infected males.

With proper treatment, the prognosis is excellent. Mortality is low, with an estimated 65,000 deaths annually due to hookworm,[29]  though those hookworm-related deaths that do occur are probably under-recognized as a consequence of the insidious nature of the disease.

In classic hookworm disease, appropriate anthelmintic treatment and iron and diet therapy typically result in complete recovery from anemia and malnutrition, though some deficits in intellectual function may persist. In endemic areas, reinfection is very likely due to repeated exposure: most patients become reinfected within months unless they are relocated to an area of significantly improved sanitation.

In cutaneous larva migrans, the larvae die even when no treatment is provided, and symptoms resolve within a few weeks to several months. Eosinophilic enteritis promptly responds to mebendazole therapy.

Anemia remains the most significant clinical consequence of hookworm infection. Hookworms are the leading cause of iron-deficiency anemia in developing countries.[26]  Severe anemia retards childhood development and intellectual performance and can cause significant disability in heavily infected communities. Vigorous labor is possible only with hemoglobin levels higher than 7 g/dL.

The timing of anemia onset depends on the patient’s pre-existing iron stores, diet, and intensity of infection. In a study involving 492 children, the prevalence of anemia and the prevalence of ferritin levels lower than 12 μg/L were 60.5% and 33.1%, respectively, in those with N americanus infection, compared with 80.6% and 58.9%, respectively, in those with A duodenale infection.[30]  In an additional study, intensity of hookworm infection was strongly associated with severity of anemia.[31]

Young women, especially those who are pregnant, and laborers are most susceptible to symptomatic anemia due to their underlying nutritional status.[8]  Adolescent girls and women of child-bearing age are at particular risk for poor outcomes such as increased maternal mortality, prematurity, low birth weight, and impaired lactation. As many as 30-54% of cases of moderate-to-severe anemia among African and Asian women are attributable to hookworm.

In addition to anemia, malabsorption may occur as a result of infection. Heavy infections can cause significant protein loss as the host loses RBCs and plasma. Adult hookworms also secrete potent inhibitors of digestive enzymes, which may contribute to malabsorption.[28]  Malabsorption leads to hypoproteinemia, which aggravates malnutrition. Malabsorption is more common in children than in adults. Anemia and protein malnutrition occur together in as many as 25% of infected individuals.

Patient education focuses on preventive measures. Walking barefoot outdoors in endemic areas should generally be discouraged; however, the effect of wearing proper footwear on hookworm transmission is likely to be overestimated. Inadequate sanitation remains a primary risk factor for hookworm infection.[32]  Improved sanitation and public health education about proper hygiene may considerably reduce the risk of infection. The WHO has resources especially designed to teach children about hookworm that may be helpful for providers in endemic areas to use in informing high-risk populations.[33]

The majority of individuals who develop hookworm infection are from known endemic areas. They frequently have a history of wearing open footwear or walking barefoot in such areas.

Most individuals with hookworm infection are asymptomatic,[17]  and diagnosis is made only by means of stool examination (see Workup). Those symptoms that do occur depend on the type of hookworm disease present (ie, classic hookworm disease, cutaneous larva migrans, or eosinophilic enteritis) and on the stage of the disease (ie, early or late).

Early symptoms of classic hookworm disease

During the first 1-2 weeks after a cutaneous infection, hookworm produces a local irritation at the site of infection, termed ground itch or dew itch.[17]  An intensely pruritic, erythematous, or vesicular rash appears, usually on the feet or hands; its severity is generally proportionate to the number of infecting larvae. This rash should be distinguished from a creeping eruption due to skin migration of the cat or dog hookworm A braziliense.

Cough and wheezing can occur about 1 week after exposure as a consequence of larval migration through the lungs. Pulmonary symptoms are uncommon and usually mild, except in severe infections. In rare cases, severe infections may give rise to Löffler syndrome, characterized by paroxysmal attacks of cough, dyspnea, pleurisy, little or no fever, and eosinophilic pulmonary infiltrates that last several weeks after the initial infection.[26]

Migration of the worms into the gastrointestinal (GI) tract may cause GI discomfort secondary to irritation. As the worms mature in the jejunum, patients may experience diarrhea, vague abdominal pain, colic, flatulence, nausea, or anorexia. These symptoms are more common with initial exposures than with subsequent exposure and typically peak between 30 and 45 days after infection.

In people who have been infected with a large burden of A duodenale through oral ingestion, Wakana syndrome may occur. This syndrome resembles an immediate-type hypersensitivity reaction and is characterized by pharyngeal itching, hoarseness, nausea, vomiting, cough, dyspnea, and eosinophilia.[26]

Later symptoms of classic hookworm disease

Mild hookworm infections are often asymptomatic. Moderate-to-heavy infections cause significant blood loss, which may manifest as melena. Once iron reserves are exhausted, anemia develops. A large worm burden and a history of poor iron intake increase the likelihood of significant anemia.

Patients with severe iron-deficiency anemia may present with lassitude, headache, palpitations, exertional dyspnea, syncope, or edema. They may also have a history of perverted taste and pica. In rare cases, anemia may provoke ischemic symptoms such as angina or claudication.

Deficits in physical and intellectual growth can occur due to anemia and protein deficiency; these deficits may be irreversible when they develop during childhood.

Cutaneous larva migrans

Infection with zoonotic hookworms, especially A. braziliense, can progress with a lateral skin migration of larvae that results in the characteristic tracts of cutaneous larva migrans (creeping eruption).[34]  This is to be distinguished from the ground itch noted in classic hookworm disease.

Eosinophilic enteritis

Eosinophilic enteritis is characterized by repeated episodes of abdominal pain in approximately 97% of affected individuals. These episodes typically occur with increasing severity and are associated with peripheral eosinophilia in almost 100% of patients and with leukocytosis in approximately 75% of patients. Extreme cases may mimic appendicitis or intestinal perforation.

Skin and pulmonary findings are minimal. Physical findings in the early (larval migration) stage of the disease differ from those in the late (established GI infection) stage.

Early signs of classic hookworm disease

An erythematous, pruritic, papulovesicular rash develops at the site of initial infection and may persist for 1-2 weeks after initial infection. Intense scratching may lead to a secondary bacterial infection, which is quite common.

When the worms break through from the venous circulation into the pulmonary air spaces, cough, fever, and a reactive bronchoconstriction may be observed, with wheezing heard on auscultation.

During the period of intestinal involvement, abdominal examination may reveal midepigastric pain on palpation. Stools may be bloody or melanotic.

Later signs of classic hookworm disease

Signs of iron-deficiency anemia are often insensitive. Patients may exhibit pallor, chlorosis (greenish-yellow skin discoloration), hypothermia, spooning nails, tachycardia, or signs of high-output cardiac failure.

Hypoproteinemia may lead to anasarca and peripheral edema.[10]  Poor skin texture, edema, and susceptibility to cutaneous infection suggest possible malnutrition. Stunted growth may be observed in children with severe infection.[35]

Cutaneous larva migrans

Cutaneous larva migrans manifests as pathognomonic, raised serpiginous tracts (creeping eruptions) with surrounding erythema that may last as long as 1 month if untreated. Lesions are most commonly seen on lower extremities but may be limited to the trunk or upper extremities, depending on the site at which the infective larvae entered the body.[36]

Intense exposure resulting in heavy parasitism can produce acute gastrointestinal hemorrhage, severe acute anemia, and congestive heart failure. An early example was an epidemic called “miner’s anemia” striking Italian laborers building the alpine Saint Gotthard railway tunnel in 1880. Today, this occurs most often in epidemics associated with breakdowns in sanitation as a result of war or famine but can also occur in especially burdened individuals from endemic areas.[25]

More commonly, children with chronic infection perform poorly in school and have decreased productivity.[37]  The etiology of this cognitive impairment is probably multifactorial, secondary to both chronic iron-deficiency anemia and protein deficiency, as well as missed learning opportunities.

Children with chronic infection may also have linear growth retardation (stunted growth).[35]  In one study, children with helminthiasis (including infection caused by hookworms and other helminths) and anemia were 8.7 times more likely to have stunted growth and 4.3 times more likely to be underweight than children without anemia and infection.[38]

In rare cases, neonatal infection with A duodenale contracted through breastfeeding may lead to fulminant GI hemorrhage.

Laboratory findings (eg, complete blood count [CBC]) may be consistent with iron-deficiency anemia. A differential count may reveal eosinophilia (1000-4000 cells/µL). Serologic tests (eg, tests for A caninum) are usually available only in research laboratories.

Stool should be examined for ova and parasites. The examination may demonstrate significant number of hookworm eggs. However, because egg laying may be delayed, stool examination should not be considered a sensitive test for identifying hookworm infection. Stool examinations may have to be repeated.

PCR-based methods for the sensitive and specific diagnosis of hookworm have been developed, but are not widely used.[39]

Other causes of iron loss and blood loss should be excluded.

Anemia is confirmed by CBC and peripheral blood smear results that demonstrate signs typical of iron-deficiency anemia. Microscopy reveals hypochromic, microcytic red blood cells (RBCs).

Upon initial infection, eosinophilia is usually present during the migratory phase before stool findings are positive.[10]  Eosinophilia is surprisingly persistent and may be due to attachment of the adult worms to the intestinal mucosa. Peak eosinophil counts are 1350-3828 cells/µL at 5-9 weeks after experimental human exposure to 45-50 infective larvae. Eosinophilia can be a clue to hookworm, as well as Strongyloides infestation, in chronically infected patients.

Eosinophilia (along with raised serum immunoglobulin E [IgE] levels) is uncommon in cases of cutaneous larva migrans but is almost universally present in cases of eosinophilic enteritis.[40]

The diagnosis is confirmed with direct microscopic analysis of fecal samples to verify the presence of hookworm eggs. The specimen is fixed in formalin and prepared as a wet mount.[41]

During early infection, results of stool studies may be normal; in rare cases, the worm or larvae may be present in the fecal sample. In patients with mature infection, eggs may be seen during stool examination. If eggs are not seen, the likelihood of clinically significant infection is very low. When infection is suspected, stool should be evaluated promptly because eggs hatch into infective larvae within 24 hours.

Direct microscopic stool examination usually reveals ovoid eggs with thin colorless shells, measuring approximately 60 ´ 40 µm. Under basic light microscopy, the eggs of N americanus and those of A duodenale appear morphologically similar. Larvae and adult worms can be distinguished by rearing filariform larvae in a fecal smear on a moist filter paper strip for 5-7 days (ie, Harada-Mori filter paper strip culture).

Distinguishing between N americanus and those of A duodenale is not critically important for choosing the type of anthelmintic drug to use, except that arrested larvae of A duodenale can enter breast milk and cause vertical transmission; these arrested larvae can also reactivate after initial treatment and again cause intestinal disease without reinfection.

Although hookworm eggs are easily distinguished from the eggs of other helminths, rhabditiform larvae are occasionally seen in old stool specimens. Differentiating the larvae of Necator or Ancylostoma organisms from those of Strongyloides organisms requires attention to the unique morphologic features, particularly the relatively short buccal cavity and prominent genital primordium of Strongyloides larvae.

Various methods (eg, ether concentration or Kato-Katz thick smear) can be used for quantitative assessments. Importantly, the Kato-Katz method requires the use of fresh stool samples so that the eggs do not die – otherwise, the observed egg count will be artificially low. The worm burden may be estimated by counting the number of eggs per gram of stool, multiplying by the daily stool weight, and dividing the result by 25,000. A worm burden of less than 25 is generally subclinical; a burden of more than 500 worms is clinically significant. Accepted intensity classifications based on eggs per gram of stool are as follows:

Table 1: WHO intensity classifications (Open Table in a new window)

In most cases, stool-concentration techniques are unnecessary, because most individuals with clinically significant infection excrete a large number of eggs. Eggs are easily detectable in unconcentrated specimens at levels of 1200/mL or higher. However, such techniques may be helpful for diagnosis of minimal infections expected during control programs. Because the intensity and prevalence of hookworm infection decrease with public health intervention, newer concentration methods (eg, FLOTAC) have some advantages over older methods.[42]

In cases of cutaneous larva migrans, stool examination is not indicated, because the diagnosis can be made clinically and because the larvae remain confined to the skin in almost all cases. In cases of eosinophilic enteritis, no eggs are found, because adult A caninum worms do not produce eggs in human hosts.

In cases of severe infection, chest radiography may show diffuse alveolar infiltrates during the migration of the larvae through the lung to the intestine. Once infection is established in the gut, imaging studies are not helpful.

In cases of eosinophilic enteritis, colonoscopy may reveal ileal and colonic ulceration and, occasionally, adult hookworms.

Most cases of classic hookworm disease can be managed on an outpatient basis with anthelmintic and iron therapy, complemented by appropriate diet. Patients with anemia and malnutrition may require both iron supplements and nutritional support (including folate supplementation). Some patients with severe anemia and congestive heart failure may require hospitalization.

Blood transfusion is indicated in rare cases of acute severe gastrointestinal (GI) hemorrhage. In patients with chronic anemia, blood transfusions (ie, packed red blood cells [RBCs]) should be administered slowly and are usually followed by a diuretic to prevent rapid fluid overload.

For patients with cutaneous larva migrans who have minimal symptoms, specific anthelmintic treatment may be unnecessary.

Eosinophilic enteritis may mimic acute appendicitis or intestinal perforation, and, in some cases, diagnosis has been made during laparotomy. However, treatment for eosinophilic enteritis is medical (ie, mebendazole administration) rather than surgical.

Specialty consultations are usually unnecessary unless the anemia is severe or blood indices are equivocal. The primary physician typically monitors anemia treatment.

Anthelmintic drugs effective against hookworms include benzimidazoles (eg, albendazole, mebendazole) and pyrantel pamoate[41] . Treatments that may be employed include the following[43] :

Table 2: WHO and CDC treatment recommendations (Open Table in a new window)

*Albendazole is markedly superior to mebendazole

Albendazole, although not approved by the US Food and Drug Administration (FDA) for hookworm therapy in the United States, continues to have the highest apparent cure rate, especially for single-dose therapy.

The Centers for Disease Control and Prevention (CDC) continues to recommend a 400-mg single dose of albendazole on its Website (June 28, 2021), but notes that albendazole is still not FDA approved for the treatment of hookworm infection. The Sanford Guide to Antimicrobial Therapy  recommends albendazole 400 mg daily for 3 days or mebendazole 100 mg twice daily for 3 days.

Although benzimidazoles are an effective chemotherapeutic option, reinfection remains a notable problem because exposure to the hookworm does not confer long-term immunity.[44]  Rapid hookworm reinfection is common in endemic areas and is made particularly problematic by the high prevalence and worm burden in untreated adults who continue to contaminate soil.

Repeated community treatment may result in an emerging drug resistance.[45]  In a Zanzibari population of children treated repeatedly over 5 years, cure and egg elimination rates both decreased significantly with time.[46]  This suggests the need for a renewed emphasis on community-wide sanitation, education, and, possibly, vaccine development (see Prevention).[47]

Because of developing resistance in areas with frequent periodic deworming (eg, Java), newer drugs to treat hookworm disease are being sought. Unfortunately, the market for new antiparasitic drugs is small. A promising alternative to albendazole is tribendimidine, a synthetic drug developed in China; in initial trials, tribendimidine appears to be equal or even superior to single-dose albendazole.[48]  Other experimental drugs in development include small-molecule inhibitors of nematode carnitine palmitoyltransferase[49] and Bacillus thuringiensis Cry5B protein.[50]

Iron replacement and nutritional supplementation (protein and vitamins, including folate) should be part of the management strategy and may have greater efficacy than anthelmintic therapy in reducing morbidity in selected populations (eg, pregnant women and patients who are not infected with HIV). Such combined therapy has been successful in Peru and Brazil but less so in Kenya.[51]

Wheezing and cough are managed with inhaled beta agonists. Steroids may cause pulmonary symptoms to become exacerbated, particularly in patients with Strongyloides infection.

Treatment in special populations

Young children

Although very rare in nonambulatory children (< 2 years), hookworm infection in this age group can carry significant mortality. A fulminant form of acute hookworm infection causing acute GI tract hemorrhage has been described in infants. The means of transmission is unknown, but likely environmental.[52]  These infants (often >2 months) present with melena or frank rectal bleeding, abdominal distention, hypotension, and profound anemia.

Experience with anthelmintic drugs is limited for children in this age group. The World Health Organization (WHO) recommends administering half the adult dosage of albendazole (200 mg) in children over 24 months with heavy hookworm infections. The dosage of pyrantel is determined on the basis of the child’s weight.

Published reports addressing the use of albendazole or mebendazole in children younger than 6 years are limited. In 2007, a pair of randomized clinical trials were conducted in Vietnam to evaluate the efficacy of mebendazole.[45]  The initial study compared the efficacy of single-dose mebendazole with that of placebo among schoolchildren aged 6-11 years. In this study, single-dose mebendazole did not significantly reduce the disease burden as determined by fecal sample egg counts.

Albendazole appears to be superior to mebendazole for curing hookworm infection in children, achieving cure rates of approximately 90% for Ancylostoma and 75% for Necator. The FDA has approved the use of 100mg mebendazole twice daily for 3 days for the treatment of hookworm in children older than 2 years. The potential benefits and risks of these agents in pediatric patients must be considered before treatment is pursued.

Pregnant and lactating women

Currently, pregnant or lactating women are recognized as being at high risk in endemic regions. The WHO recommends deworming treatment using single-dose albendazole or mebendazole during the second or third trimester for pregnant women with heavy hookworm infections.[43]

A significant correlation has been observed between maternal anemia (nutritional or parasitic) and an increased risk of bearing premature and low-birth-weight (LBW) infants.[53]  In comparison with neonates of average weight, LBW infants subsequently have higher overall morbidity and mortality.

One strategy for reducing the incidence of low birth weight is prenatal treatment of mothers for presumptive parasitic infections. In a clinical trial conducted among pregnant mothers in Peru, where the prevalence of hookworm infection is high, prenatal treatment with mebendazole in addition to iron supplementation brought about a small but significant reduction in the incidence of very-LBW neonates.[51]

Community control of hookworm infection is difficult unless substantial improvements in socioeconomic conditions, sanitation, education, and footwear availability can be achieved. Successful programs have included economic, sanitary, and mass-treatment components. Current WHO recommendations for hookworm infection include annual (in communities where prevalence is above 20%) or biannual (in communities where prevalence is above 50%) mass therapy with single-dose albendazole or mebendazole to lower the overall worm burden until conditions permit a multicomponent physical and educational program. Community leaders should be trained about WHO recommendations.[43]

Cost studies comparing various management strategies favor community-wide, single-dose albendazole chemotherapy at intervals of 12-18 months. Some programs have been more intensive, with dosing frequency up to quarterly in school children for highly endemic areas.[16]

With regard to sanitation, sanitary excreta disposal is the most effective deterrent, but it is not feasible in many developing countries. Wearing footwear cannot entirely prevent infection because larvae can penetrate any skin surface that comes in contact with contaminated soil. In addition, A duodenale larvae can be ingested.

Mass chemotherapy remains a mainstay of hookworm control strategies. It should be kept in mind that mass or targeted chemotherapy programs may not control hookworm infection, because reinfection is common in endemic areas, and dormant extraintestinal larvae of A duodenale may be resistant to currently available anthelmintic agents.

A concern with mass chemotherapy is that continued use of drugs may lead to reduced efficacy; treatment failures have been observed.[12]  Most recently, multiple drug resistance has been observed in canine hookworm (Ancylostoma caninum) populations, indicating that widespread drug resistance is a growing concern in the treatment and control of hookworm.[54]  Anthelmintic treatment delivered as part of a Ugandan national helminth control program decreased infection and morbidity among schoolchildren and improved hemoglobin concentration.

Although school-based deworming programs probably will not adequately control the prevalence of hookworm infection, they can have a substantial effect on children’s nutritional status, cognitive development, and productivity. Children with hookworm anemia have considerably lower scores on cognitive function tests and exhibit delayed acquisition of language and motor skills. When the infection and the associated anemia are treated, their educational performance and productivity improve.[55]  At a population level, improvement in health outcomes has been disappointing, as referenced in numerous recent reviews.[56]

As understanding of the immunoepidemiology and the molecular pathogenesis of hookworm infection improves,[57]  identification of a safe and effective vaccine remains a high priority,[47]  although achieving progress remains scientifically and economically challenging.[58]  The development of an efficacious vaccine requires molecular targeting of both larval and adult stages in order to break the reproductive cycle. In this regard, the Ancylostoma-secreted proteins (ASPs) are one group of potentially promising targets.[29]

In a hamster model using N. americanus ASP-2 (Na -ASP-2) hookworm vaccine, encouraging results were achieved with respect to lowering worm burdens and inhibiting growth delay. In 2006, a phase I clinical trial of Na -ASP-2 vaccine demonstrated that the vaccine was both safe and well tolerated.[59]  In addition, the vaccine evoked sustained cellular immune responses and elevated immunoglobulin titers. Unfortunately, this vaccine has been withdrawn from development because of urticarial reactions in previously infected recipients.[16]

More recently, a bivalent vaccine targeting Na-Glutathione S-transferase-1 (Na-GST-1) and Na-Aspartic Protease-1 (Na-APR-1) has been developed. As of September 2020, this vaccine has been indicated to be safe and potentially effective in phase I clinical trials.[15]  Phase II clinical trials are currently underway.[60]

The recent characterization of the N. americanus genome has potential for advancing knowledge of therapeutic and preventive strategies of control.[61]  Other larval and adult stage targets have been identified, and additional preclinical studies are being conducted. With additional investigation and further trials, these vaccines will offer an appealing novel strategy to prevent hookworm infections globally.

It is to be hoped that the combined use of periodic deworming, improved sanitation, and an (at least partially) effective hookworm vaccine will decrease the medical, social, and economic burden of anemia due to hookworm in developing countries. The emergence of benzimidazole resistance is a growing concern, and new drugs are being sought. A promising agent is tribendimidine, which was first synthesized in China in the 1980s and has had promising results in ongoing trials.[48]

Integrated control of hookworm infection together with other helminth infections can be provided with a package of medicines costing approximately $0.50 per patient per year.[23]  Such dual therapy has been shown effective in various geographic contexts.[62]  Major partnerships of organizations are coordinating integrated management through the Global Network for Neglected Tropical Disease Control.[63]  Such efforts provide hope for improving the health and economic development of millions worldwide.

The recommended procedure is to repeat the stool examination using a concentration technique after 2-3 weeks; positive results indicate the need for retreatment. The entire course of iron therapy must be completed to replenish iron stores, even after hemoglobin values return to normal.

It is important to be alert for possible reinfection, which is common in endemic areas. Dormant extraintestinal larvae of A duodenale may be resistant to currently available anthelmintic agents (which may have poor systemic absorption) and may be responsible for relapse.

As worm burden decreases in both individuals and population, more sensitive testing methods such as PCR will likely be required to ensure eradication.[64]

Therapy for parasitic infestations is based on the specific parasite and the particular phase of the disease. The treatment of classic hookworm infection has the following 2 components:

• Correcting the anemia, which is usually achieved by means of iron therapy and proper diet

• Expelling the intestinal parasites

In rare cases (eg, acute severe gastrointestinal [GI] hemorrhage), blood transfusion may be needed to correct anemia.

Anthelmintic drugs effective against hookworms include pyrantel pamoate and benzimidazoles (eg, albendazole, mebendazole). Benzimidazoles are the most convenient and effective drugs for treating hookworm disease. Other older agents are also effective but may have lower clearance rates.

Class Summary

Anthelmintics are poorly absorbed, relatively nontoxic broad-spectrum agents that act by inhibiting tubulin polymerization. They have shown high clearance rates.

Because biochemical pathways in these parasites differ from those in human hosts, toxicity is directed toward the parasite, egg, or larvae. The mechanism of action varies within the drug class. Antiparasitic actions may include the following:

- Inhibition of microtubules, causing irreversible block of glucose uptake

- Inhibition of tubulin polymerization

- Depolarizing neuromuscular blockade

- Cholinesterase inhibition

- Increased cell membrane permeability, resulting in intracellular calcium loss

- Vacuolization of the schistosome tegument

- Increased cell membrane permeability to chloride ions via alteration of chloride channels

Albendazole (Albenza)

Albendazole is a benzimidazole carbamate that inhibits tubulin polymerization, resulting in degeneration of cytoplasmic microtubules. It decreases production of adenosine triphosphate (ATP) in the worm, causing energy depletion, immobilization, and finally death. Albendazole is converted in the liver to its primary metabolite, albendazole sulfoxide; less than 1% of this metabolite is excreted in urine. The plasma level rises substantially (as much as 5-fold) when the drug is ingested after a high-fat meal.

Albendazole is approved by the US Food and Drug Administration (FDA) for treatment of hookworm infection but is considered investigational. A single 400-mg dose is the treatment of choice; it has a high eradication rate and is easy to administer. At such a dosage, albendazole is selectively toxic to parasites because binding to parasite β-tubulin occurs at a much lower concentration than binding to mammalian protein. Because the drug acts locally on worms within the GI tract, its action is not dictated by its systemic concentration.

Mebendazole (Vermox)

Mebendazole inhibits microtubule polymerization by binding to cytoplasmic β-tubulin. By affecting the intestinal cells of the parasite, it prevents the organism from using nutrients and thus essentially starves it to death.

Mebendazole is recommended for treating eosinophilic enteritis. A 3-day course has a reported cure rate of 95% and egg reduction rate of 99.9%. Single-dose therapy is often advocated but may not be as effective as single-dose albendazole. At recommended dosages, mebendazole is selectively toxic to parasites because binding to parasite β-tubulin occurs at a much lower concentration than binding to mammalian protein. Because the drug acts locally on worms within the GI tract, its action is not dictated by its systemic concentration.

Repeat stool examination with a concentration technique is recommended after 2 weeks; if the examination yields positive results, retreatment is indicated. No fasting or purging is required. The tablet may be chewed, swallowed, or crushed and mixed with food.

Pyrantel pamoate (Pin-X, Pamix, Reeses Pinworm Medicine)

Pyrantel pamoate is a depolarizing neuromuscular blocking agent that inhibits cholinesterases, resulting in spastic paralysis of the worm. It is FDA-approved for hookworm infection but is considered investigational for this condition.